Dingwell K S, Brunetti C R, Hendricks R L, Tang Q, Tang M, Rainbow A J, Johnson D C
Department of Pathology, McMaster University, Hamilton, Ontario, Canada.
J Virol. 1994 Feb;68(2):834-45. doi: 10.1128/JVI.68.2.834-845.1994.
Herpes simplex virus (HSV) glycoproteins E and I (gE and gI) can act as a receptor for the Fc domain of immunoglobulin G (IgG). To examine the role of HSV IgG Fc receptor in viral pathogenesis, rabbits and mice were infected by the corneal route with HSV gE- or gI- mutants. Wild-type HSV-1 produced large dendritic lesions in the corneal epithelium and subsequent stromal disease leading to viral encephalitis, whereas gE- and gI- mutant viruses produced microscopic punctate or small dendritic lesions in the epithelium and no corneal disease or encephalitis. These differences were not related to the ability of the gE-gI oligomer to bind IgG because the differences were observed before the appearance of anti-HSV IgG and in mice, in which IgG binds to the Fc receptor poorly or not at all. Mutant viruses produced small plaques on monolayers of normal human fibroblasts and epithelial cells. Replication of gE- and gI- mutant viruses in human fibroblasts were normal, and the rates of entry of mutant and wild-type viruses into fibroblasts were similar; however, spread of gE- and gI- mutant viruses from cell to cell was significantly slower than that of wild-type HSV-1. In experiments in which fibroblast monolayers were infected with low multiplicities of virus and multiple rounds of infection occurred, the presence of neutralizing antibodies in the culture medium caused the yields of mutant viruses to drop dramatically, whereas there was a lesser effect on the production of wild-type HSV. It appears that cell-to-cell transmission of wild-type HSV-1 occurs by at least two mechanisms: (i) release of virus from cells and entry of extracellular virus into a neighboring cell and (ii) transfer of virus across cell junctions in a manner resistant to neutralizing antibodies. Our results suggest that gE- and gI- mutants are defective in the latter mechanism of spread, suggesting the possibility that the gE-gI complex facilitates virus transfer across cell junctions, a mode of spread which may predominate in some tissues. It is ironic that the gE-gI complex, usually considered an IgG Fc receptor, may, through its ability to mediate cell-to-cell spread, actually protect HSV from IgG in a manner different than previously thought.
单纯疱疹病毒（HSV）糖蛋白E和I（gE和gI）可作为免疫球蛋白G（IgG）Fc结构域的受体。为研究HSV IgG Fc受体在病毒发病机制中的作用，通过角膜途径用HSV gE或gI突变体感染兔和小鼠。野生型HSV-1在角膜上皮产生大的树枝状病变及随后的基质疾病，导致病毒性脑炎，而gE和gI突变病毒在上皮产生微小点状或小树枝状病变，且无角膜疾病或脑炎。这些差异与gE-gI寡聚体结合IgG的能力无关，因为这些差异在抗HSV IgG出现之前以及在IgG与Fc受体结合不良或根本不结合的小鼠中就已观察到。突变病毒在正常人成纤维细胞和上皮细胞单层上产生小斑块。gE和gI突变病毒在人成纤维细胞中的复制正常，突变病毒和野生型病毒进入成纤维细胞的速率相似；然而，gE和gI突变病毒在细胞间的传播明显慢于野生型HSV-1。在以低病毒感染复数感染成纤维细胞单层并发生多轮感染的实验中，培养基中存在中和抗体导致突变病毒产量大幅下降，而对野生型HSV的产生影响较小。看来野生型HSV-1的细胞间传播至少通过两种机制发生：（i）病毒从细胞释放，细胞外病毒进入相邻细胞；（ii）病毒以一种对中和抗体有抗性的方式穿过细胞连接。我们的结果表明，gE和gI突变体在后者这种传播机制上存在缺陷，这表明gE-gI复合物促进病毒穿过细胞连接的可能性，这种传播方式可能在某些组织中占主导。具有讽刺意味的是，通常被认为是IgG Fc受体的gE-gI复合物，可能通过其介导细胞间传播的能力，实际上以一种与先前认为的不同的方式保护HSV免受IgG的影响。
